Abstract The long-term goal of this project is to develop a compact, label-free, low-cost optical device for imaging epithelial tissues in cancer detection and diagnosis. 80-90% cancers arise as carcinomas in epithelial tissues. Various high resolution optical imaging techniques and devices have been developed for early detection and diagnosis of epithelial diseases, but most of them are complicated and expensive, not suitable for point-of-care applications and low resource setting environment. We propose to develop a structured chromatic light sheet microscope. The key innovation is the use of a white LED array to generate structured chromatic light sheet, eliminating the need of external bulky light source and scanner or spatial light modulator to obtain 3D tissue image. Another key innovation is the method of chromatic slit confocal detection using a linear variable filter to block the out-of-the-light-sheet light to improve image contrast and resolution. The image resolution and contrast will be further improved by taking and processing three images modulated with phase-shifted structured light. It is also expected that the image resolution and contrast in deeper layers can be improved by focusing and imaging a long wavelength light sheet deeper into the tissue. In addition, volumetric image can be obtained by projecting structured light sheets sequentially through the focal plane with 2D LED array. In this project, we will first develop a structured chromatic light sheet microscope (Aim 1), and then evaluate the performance of the prototyped structured chromatic light sheet microscope in imaging epithelial tissue (Aim 2). With the knowledge gained in Aims 1 and 2, we will also develop and evaluate a handheld structured chromatic light sheet microscope for epithelial tissue imaging (Aim 3). The concepts of chromatic light sheet and chromatic slit confocal detection will have profound impact on light scattering imaging and potential applications in detection and diagnosis of epithelial cancers. This project will result in an effective clinical tool for early detection of skin and oral cancers, which will significantly reduce disease progression and mortality and improve quality of life. Further, this affordable tool will be very practical for low-resource settings to reduce the burden of skin and oral cancers in low- and middle- income countries (LMICs). In addition, the proposed microscope could enable improved localization of biopsy sites and delineation of surgical margins, which will reduce the need for repeat and random biopsies.